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- Title
An antibody from single human V<sub>H</sub>-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.
- Authors
Luo, Sai; Zhang, Jun; Kreutzberger, Alex J. B.; Eaton, Amanda; Edwards, Robert J.; Jing, Changbin; Dai, Hai-Qiang; Sempowski, Gregory D.; Cronin, Kenneth; Parks, Robert; Ye, Adam Yongxin; Mansouri, Katayoun; Barr, Maggie; Pishesha, Novalia; Williams, Aimee Chapdelaine; Vieira Francisco, Lucas; Saminathan, Anand; Peng, Hanqin; Batra, Himanshu; Bellusci, Lorenza
- Abstract
SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several VH1-2/Vκ1-33–based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient–derived VH1-2–based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy–based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.
- Publication
Science Immunology, 2022, Vol 7, Issue 76, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.add5446